Generic-to-generic Lamotrigine Switches in People With Epilepsy: The Randomized Controlled Equivalence Among Generic Antiepileptic Drugs (EQUIGEN) Trial

Sol Ahn, Mercer University College of Pharmacy

According to the American Epilepsy Society, there has been a physician and patient perception that generic antiepileptic drugs are not always equivalent to brand products or other generic medications. [1]

In a systemic review article of nine randomized controlled trials and seven prospective observational studies assessing seizure outcomes from use of brand-name and generic antiepileptic medications, it is stated that the available evidence does not suggest an association between loss of seizure control and generic substitution of antiepileptic drugs. [2]

Generic-to-generic Lamotrigine Switches in People With Epilepsy: The Randomized Controlled EQUIGEN Trial [3]
Design Randomized, controlled, double-blind, crossover trial; N= 33
Objective To study the effects of switching between two disparate generic immediate-release lamotrigine products in patients with epilepsy
Study Groups Sequence one (n= 14); sequence two (n= 19)
Methods Eligible patients were randomly assigned to one of two treatment sequences (sequence one or sequence two), comprising four study periods of 14 days each. During each 14-day treatment period, patients received balanced doses of an oral generic lamotrigine product every 12 hours (200 to 800 mg total, identical to lamotrigine dose prior to study enrolment). After each 14-day period, patients were crossed over to receive the other generic product. First assessments were done in study periods one and two, and second assessments were done in study periods three and four.
Duration Between April 25, 2013 to Aug 12, 2014
Primary Outcome Measure Bioequivalence between the generic products, which was assessed at the end of the study through a comparison of maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) for each product
Baseline Characteristics Sequence one (n= 14) Sequence two (n= 19)
Age, years 42.7 49.4
White, n (%) 13 (93%) 18 (95%)
African-American, n (%) 1 (7%) 1 (5%)
Men, n (%) 3 (21%) 8 (42%)
Women, n (%) 11 (79%) 11 (58%)
Weight, lb 183.1 178.8
Duration of epilepsy, years 25.5 25.5
Epilepsy diagnosis
Generalized, n (%) 3 (21%) 3 (16%)
Focal, n (%) 10 (71%) 15 (79%)
Non-classified, n (%) 1 (7%) 1 (5%)
Lamotrigine dose, mg
100 mg every 12 hours, n (%) 3 (21%) 8 (42%)
200 mg every 12 hours, n (%) 6 (43%) 9 (47%)
300 mg every 12 hours, n (%) 3 (21%) 2 (11%)
400 mg every 12 hours, n (%) 2 (14%) 0
Results Generic lamotrigine – one Generic lamotrigine – two
First assessment (n= 33) Second assessment (n= 33) Mean % within participant change First assessment (n= 33) Second assessment (n= 33) Mean % within participant change
AUC (ug∙mL/min) 2723 (1145) 2727 (1173) 1.09% (-4.6 to 6.8) 2710 (1129) 2704 (1200) -0.58% (-3 to 4.1)
Cmax (ug/mL) 5.03 (1.8) 5.02 (1.9) 0.58% (-4.5 to 5.6) 4.96 (1.9) 4.095 (1.9) 0.73% (-4 to 5.5)
Data are mean (SD) or mean (95% CI); data are dose-normalized to 100 mg.
Adverse Events Common Adverse Events: N/A
Serious Adverse Events: seizure clusters (2.9%)
Percentage that Discontinued due to Adverse Events: 2.9%
Study Author Conclusions Disparate generic lamotrigine products in patients with epilepsy showed bioequivalence with no detectable difference in clinical effects, confirming that US Food and Drug Administration bioequivalence standards are appropriate.

The study results show that two disparate generic lamotrigine products have bioequivalence in Cmax and AUC. Furthermore, these data show that switching between generic products was not associated with loss of seizure control or with any change in adverse effects in this study. Possible limitations of the study include the small sample size and baseline seizure frequency, both of which were not sufficiently powered to detect a difference in seizure control. Additionally, patients who might have previously had changes in seizure frequency or adverse events with generic switching could be less likely to volunteer for a clinical study involving generic substitution.

References

[1] American Epilepsy Society. https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/186836. Accessed on April 7, 2016.

[2] Kesselheim AS, Stedman MR, Bubrick EJ, et al. Seizure outcomes following the use of generic versus brand-name antiepileptic drugs: a systematic review and meta-analysis. Drugs. 2010;70(5):605-21.

[3] Privitera MD, Welty TE, Gidal BE, et al. Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial. Lancet Neurol. 2016;15(4):365-72.

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